Cohen B D, Siegall C B, Bacus S, Foy L, Green J M, Hellström I, Hellström K E, Fell H P
Molecular Immunology Department, Bristol-Myers Squibb, Pharmaceutical Research Institute, Seattle, WA 98121, USA.
Biochem Soc Symp. 1998;63:199-210.
Members of the epidermal growth factor (EGF) family of tyrosine kinase receptors are involved in the regulation of cell growth and differentiation, and are found to be expressed in many types of cancers. Activation of these receptors can be elicited by multiple ligands, resulting in the formation of a spectrum of heterodimer complexes and a number of biological outcomes. A clear demonstration of biological activation by a single complex has been difficult to address because of the endogenous expression of HERs (human EGF-like receptors) in many cell lines. We have generated a collection of cell lines expressing all HERs alone or in all pairwise combinations in a clone of NIH 3T3 cells (3T3-7d) devoid of detectable EGF receptor family members. Transformation, as measured by growth in soft agar, only occurred in cells expressing two different HER family members. Transformation with activated Neu and the rate of in vivo tumour formation were also correlated with the expression of multiple HERs in the same cell. To further our understanding of the role of heterodimer signalling, we demonstrated that, within a breast carcinoma cell line, activation of HER-3 results in cellular differentiation, prolonged activation of extracellular-signal-related kinase 1 (ERK1) activity and an increase in p21CIP1/WAF1 nuclear staining. In contrast, activation of HER-4 is mitogenic, induces transient activation of ERK1 activity and decreases the nuclear staining of p21CIP1/WAF1. These differences in biochemical and biological responses are correlated with the contrasting abilities of HER-3 and HER-4 to be down-regulated from the cell surface. The cell-surface localization of HER-3 does not change in response to ligand, whereas activation of HER-4 results in a loss of cell-surface staining followed by accumulation into a perinuclear compartment.
酪氨酸激酶受体的表皮生长因子（EGF）家族成员参与细胞生长和分化的调控，且在多种癌症类型中均有表达。这些受体的激活可由多种配体引发，从而形成一系列异二聚体复合物并产生多种生物学结果。由于许多细胞系中内源性表达人表皮生长因子样受体（HERs），因此很难明确证明单一复合物的生物学激活作用。我们已构建了一组细胞系，这些细胞系在缺乏可检测到的EGF受体家族成员的NIH 3T3细胞克隆（3T3-7d）中单独表达或两两组合表达所有HERs。通过软琼脂生长测定的转化仅发生在表达两种不同HER家族成员的细胞中。用活化的Neu转化以及体内肿瘤形成率也与同一细胞中多种HERs的表达相关。为了进一步了解异二聚体信号传导的作用，我们证明，在乳腺癌细胞系中，HER-3的激活导致细胞分化、细胞外信号调节激酶-1（ERK1）活性的持续激活以及p21CIP1/WAF核染色增加。相比之下，HER-4的激活具有促有丝分裂作用，诱导ERK1活性的瞬时激活并降低p21CIP1/WAF1的核染色。这些生化和生物学反应的差异与HER-3和HER-4从细胞表面下调的不同能力相关。HER-3的细胞表面定位不会因配体而改变，而HER-4的激活导致细胞表面染色丧失，随后积聚到核周区室。
